Frontiers in Immunology (Jun 2021)
Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy
- Genevieve E. Martin,
- Genevieve E. Martin,
- Debattama R. Sen,
- Debattama R. Sen,
- Matthew Pace,
- Nicola Robinson,
- Jodi Meyerowitz,
- Emily Adland,
- John P. Thornhill,
- John P. Thornhill,
- Mathew Jones,
- Ane Ogbe,
- Lucia Parolini,
- Natalia Olejniczak,
- Panagiota Zacharopoulou,
- Helen Brown,
- Christian B. Willberg,
- Christian B. Willberg,
- Nneka Nwokolo,
- Julie Fox,
- Julie Fox,
- Sarah Fidler,
- Sarah Fidler,
- W. Nicholas Haining,
- W. Nicholas Haining,
- John Frater,
- John Frater
Affiliations
- Genevieve E. Martin
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Genevieve E. Martin
- Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia
- Debattama R. Sen
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- Debattama R. Sen
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Matthew Pace
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Nicola Robinson
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Jodi Meyerowitz
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Emily Adland
- Department of Paediatrics, University of Oxford, Oxford, United Kingdom
- John P. Thornhill
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- John P. Thornhill
- Division of Medicine, Wright Fleming Institute, Imperial College, London, United Kingdom
- Mathew Jones
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Ane Ogbe
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Lucia Parolini
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Natalia Olejniczak
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Panagiota Zacharopoulou
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Helen Brown
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Christian B. Willberg
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Christian B. Willberg
- Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom
- Nneka Nwokolo
- Chelsea and Westminster Hospital, London, United Kingdom
- Julie Fox
- Department of Genitourinary Medicine and Infectious Disease, Guys and St Thomas’ National Health Service (NHS) Trust, London, United Kingdom
- Julie Fox
- 0King’s College National Institute of Health Research (NIHR) Biomedical Research Centre, London, United Kingdom
- Sarah Fidler
- Division of Medicine, Wright Fleming Institute, Imperial College, London, United Kingdom
- Sarah Fidler
- 1Imperial College NIHR Biomedical Research Centre, London, United Kingdom
- W. Nicholas Haining
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- W. Nicholas Haining
- 2Discovery Oncology and Immunology, Merck Research Laboratories, Boston, MA, United States
- John Frater
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- John Frater
- Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom
- DOI
- https://doi.org/10.3389/fimmu.2021.647688
- Journal volume & issue
-
Vol. 12
Abstract
T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial – but not complete – normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.
Keywords
